Unprotected sexual intercourse accounts for the vast majority of new HIV infections worldwide. A disproportionate number of these infections now occur in women as a consequence of both physiological and behavioral factors. The severity of this problem begs for the development of safe and effective chemical barriers ("topical microbicides") women can use to prevent mucosal HIV infection. Five lines of evidence strongly support the concept of using CCR5 ligands/chemokines as the antiviral agent in these barrier. Five lines of evidence strongly support the concept of using CCR5 ligands/chemokines as the antiviral agent in these barriers. First, these chemokines inhibit HIV entry by two mechanisms: competitive inhibition of virus of virus interactions with CCR5 and the induction of receptor down regulation. Second, CCR5 is a major determinant for the mucosal transmission of HIV for the mucosal transmission of HIV and its absence provides strong natural resistance to infection. Third, the population of CCR5 ligands is associated with innate resistance to HIV infection. Fourth, derivatives of a CCRR5 ligand prevent HIV infection in human epithelial tissue models for mucosal infection. Finally, there are no health problems associated with the loss CCR5. Taken together, these findings indicate that a chemokine-based topical microbicide should be highly effective barriers against vaginal HIV infection that are safe enough for repeated self application. Accordingly, our central hypothesis for this project is that an effective biological barrier against vaginal HIV transmission can be successfully formulated with a synthetic CCR5 LIGAND, -2 RANTES, and a non-phospholipid liposome1 vehicle, Novasomes. Aim 1 will be to produce and characterize the antiviral properties of -2 RANTES/Novasomes formulations while Aim 2 will e test the vaginal effects of the formulations in animal models. If we are successful, a formulation will be evaluated for efficacy in a R5 SHIV (BA-L)/rhesus macaque model in Project 3 of this program.